Novartis: Jennifer Brogdon
“There is no script or playbook for this scenario—but we felt that we were mapping a new landscape in medicine."
Fight fire with fire. Like the cancer cells they target, cellular therapies have the potential to migrate, expand and adapt their behavior.
Using engineered T-lymphocytes to battle cancer has already yielded results for patients: “Initially, we saw CAR-Ts used in patients with literally kilograms of tumor burden. After [CAR-T] therapy it was melting away,” describes Dr. Jennifer Brogdon, Head of Cell and Gene Therapies at Novartis.
The first demonstration that T cells taken from patients [autologous] could be engineered to target B cell malignancies came from Carl June’s group at UPenn: “There were two papers published in the summer of 2011, detailing the experience of three CLL patients who were treated with a CD19 targeting chimeric antigen receptor T-cell [CAR-T]. Within a month of the publication, Novartis was already talking to the researchers at UPenn,” explains Brogdon, who was on the internal diligence team at Novartis.
A trained immunologist, who studied antigen presentation for her doctoral work, Brogdon had been spearheading cancer immunotherapies within Novartis prior to 2012. Yet when she saw the early CAR-T data, she was in awe: “I was at Penn the day that Carl [June] announced the news that Emily Whitehead's bone marrow was in remission. This was a solidifying moment where I felt like this modality would be bigger than we could have imagined.”
Brogdon and a growing team at Novartis quickly pivoted, entering the race to develop the first FDA-approved CAR T-cell therapy for cancer patients: “To see this large organization [Novartis] so swiftly pivot to develop CTL019—it was incredible,” she remembers. In 2016, Novartis was able to replicate early UPenn results in larger clinical trials: showing an 83% remission rate in children with B-ALL at 3 months. A year later the CD19 targeting CAR-T, Kymriah (CTL-019), became the first FDA-approved cell therapy for patients with B-ALL. “There were definitely several company parties afterwards,” says Brogdon with a chuckle. “Across the different campuses they also had big Kymriah posters so that everyone felt like they were sharing in the achievement.”
In the 8 years following Kymriah’s approval, the cell therapy space has exploded. There are six FDA-approved products for cancer patients with hematologic malignancies, all of which target antigens on B-cells [BCMA or CD19]. Many earlier-stage companies developing CD19/BCMA CAR-Ts are now shifting their focus to address B-cell driven autoimmune diseases like lupus erythematosus.
While there is a rich (many would say overcrowded) pipeline of autologous therapies for B-cell driven cancers, solid tumors remain elusive for this modality. Durable allogeneic (off the shelf) therapies have been similarly difficult to produce.
In our interview, Brogdon discusses the challenges facing the cell therapy field and the progress made in manufacturing autologous products (including Novartis’ T-Charge approach). She also describes opportunities for “next-gen” therapies: durable allogeneic cells, in vivo T-cell engineering, logic gating, NK or Treg therapies, and novel solid tumor targets.
At the forefront of one of the most cutting-edge sectors in biopharma, Brogdon reflects that her career in science started at the bottom of a lake: “I initially got interested in biology in high school…I was able to do a longitudinal science project focused on the biology of zooplankton,” she remembers. Imbued with a love of tiny organisms, she went on to study microbiology in college and earn a PhD in immunobiology from Duke. During our interview she shares high and low points during training, strategic moves she made to land a job in industry, and tips for operating in a large organization like Novartis. The complexity of her work aside, her motivation is simple: “I came from a family of caregivers. My dad was a pastor and carpenter, and my mom was a nurse… from the very beginning, I viewed science as my way to have an impact on patients.”
With one cell therapy approval under her belt already, and several clinical stage development candidates in the pipeline, Brogdon has succeeded in her childhood ambition to help patients. Yet the work is not done: “It is up to us to build on early signals of efficacy and tackle different components of what is currently limiting in the cell therapy field.”
Below is an interview with Jennifer Brogdon, Head of Cell and Gene Therapies at Novartis:
What initially made you interested in science? Were there any early mentors that pushed you towards becoming a scientist?
I became interested in biology during my freshman year of high school. I was able to do a longitudinal science project focused on zooplankton. Each year I got to build on that science project and present the results at a science fair. For example, there was a power plant on a lake nearby to where I lived…I asked: how does efflux from the plant affect the ecosystem [pH, temperature] of the lake and the function of the zooplankton? I ended up getting a Navy Science Award for this project during my senior year. My biology teacher, Mr. Robinson, really fostered my curiosity about how things work and function. I got grounded in curiosity driven science at a young age, which was super cool.
When I went off to college to get my Bachelor of Science degree, I started studying microbiology and was fascinated by these tiny organisms. I was looking for some part time work to offset the cost of college, and funny enough there was a lab studying the same zooplankton that I had done experiments on [in high school]. So, I spent a semester or two working there. I loved it!
What did you study in your PhD, and then post-doc years? Did you plan to have a career in academia?
As I’m taking college classes [University of Illinois], I realized quickly that I enjoyed every lab course: biology, chemistry, organic chemistry, microbiology. I really fell in love when I took an immunology lab class. I felt I was witnessing “crazy” things on the bench, such as B cells producing antibodies to different antigens. At that point, I decided I wanted to get a PhD; intuitively I felt that science was something I should build upon. I also had some great teaching fellows during my college science courses. In fact, the TA for my immunobiology course went to Duke for her post-doc and I [unintentionally] followed her there for my PhD training.
[Did your family encourage you towards science specifically?]
I came from a family of caregivers. My dad was a pastor and carpenter, and my mom was a nurse. My older sister also went to nursing school, so I grew up surrounded by people who cared for their community. I did not like blood, so medicine was out of the question for me! However, I really felt I wanted to use science to help people. From the beginning, I viewed science as a way to have an impact on patients.
[What were some high and low points during your scientific training]
I set out to get a PhD in microbiology and immunology, which was a combined department at the time. I began studying human T cell biology, and structural interactions between CD4 and MHC class II molecules. My thesis work investigated how these interactions changed T cell function. One high point was just that we had a great community of people in the lab who were a lot of fun. We worked hard and played hard. Often people would be in lab till 11 o'clock at night; however, we would also play volleyball as a work break in between experiments.
A low point was trying to get my thesis work started. My thesis advisor thought she was giving me a project that was going to be straightforward and easy, as it was a natural evolution of her postdoc work at Harvard. It was not. I was tasked with making 50 different point mutations in the HLA DR beta chain and re-expressing them in different cell lines. This was a time when plasmid production, cloning and transfection were not straightforward. There was definitely a period of time when I kept coming up against a wall—trying to just figure out the tools I could use to actually do interesting science. Ultimately, there was a bit of serendipity: I went to a lab in Wisconsin to learn how to grow human T cell clones with antigen specificity, which was a technique that moved the needle on my specific project.
[On tools in immunology]
My PhD was in the early 90s, so the tools were limited. We were still using gel-based sequencing methods and had to read out the sequences manually. There were some good HLA-specific antibodies, but antibodies for other targets were not readily available. At this time, some professors at Duke were even using HLA-specific antibodies that came from immunizing themselves with cells from other faculty members—pretty crazy to imagine now! Even mini-preps were laborious, and I had to use hundreds of cesium chloride gradients to purify DNA of the different HLA mutations I was studying. Immunology has evolved so much over the past couple decades.
What factors led to Novartis in 2004/2005? What were some initial things that you were working on?
When I was doing my PhD [early 1990s] leaving academia to go to industry was taboo. It was frowned upon. I think we are in a different world now. Academia now does so much translational work, which is often a collaboration with industry. In my opinion, this has been a rather sizable change in the past 30 years. I went to Yale for my post-doc with the intention of transitioning to industry. Yale even had some resources for post-docs who were considering transitioning to industry or biotech. However, in the early 2000s there were not a huge number of companies hiring in immunology. I was also trying to stay in the New England area for personal reasons, which made the job search even more restricted.
This [time] was before CTLA4 and PD-1 monoclonal antibodies were developed, so immunologists were not yet in high demand. However, I was able to get an interview at Novartis for a job working on Th1 and Th2 cells—the area of focus for my doctoral work. Before my interview I remember discussing Novartis with my mom, who was a nurse in Illinois supporting some clinical trial work. She had interacted with folks from Novartis as part of a heart failure trial and had a very high opinion of the company—its employees and their level of scientific rigor.
When I interviewed [at Novartis] I also met an immunologist from Laurie Glimcher’s lab, and we were like two peas in a pod. We totally geeked out on science. Any fears about “missing out” on cool science by going to industry were totally allayed. I had a really fun interview meeting with the entire team—I was even working on some unpublished work [as a post-doc] that an interviewer at Novartis had spent some time pursuing [at another company]. It was a great experience.
[When you first got to Novartis, what were some initial lessons?]
There were a lot of lessons to learn right away. But I was energized because immediately I took my primary T cell expertise and designed a high throughput screening [HTS] assay where we screened a million compounds against primary T cells.
In academia I went from working in 96 well plates to using 1536 well plates on robotic machines based in the Novartis San Diego facility. We completed this screen in the first 1.5 years I was at the company. It was amazing and I loved it. But there were other struggles. For example, in industry we use acronyms like crazy—there was a language learning curve to even understand what people were talking about in meetings. We now have an internal cheat sheet for acronyms in drug discovery at the company. There is also a much higher level of scientific rigor. We are developing things that will go into patients: so, I had to become an even better scientist.
[What were some early successes?]
In the large T cell screen, we found some interesting hits and partnered with an external chemo-proteomics company for target identification. I then moved into immuno-oncology at a time when Novartis was not focused on this area—but I wanted to try to push the boundaries and it indeed led to some interesting publications. For example, we had a nice JEM paper on GITR-agonist antibodies and redefining the role of the Fc component. This was work we published back-to-back with a similar story from Jim Allison’s lab.
What were your early interests and exposure to cell therapy?
There were two papers published on the in the summer of 2011, detailing the experience of three CLL patients who were treated with a CD19 CAR-T at the University of Pennsylvania. Within a month of the publication, Novartis was already talking to these researchers and clinicians, and had started internal diligence. By the end of 2011 I was on the diligence team, and we signed the deal with Penn in August of 2012. Because I trained as a T cell immunologist and had been working in IO for several years at this point, Novartis felt I had the expertise to get involved. Personally, I felt like this was a project made in heaven for me. I was lucky enough to end up on the team that brought CTL019 [Kymriah] forward to the ODAC [Oncologic Drugs Advisory Committee of the U.S. Food & Drug Administration], and later to approval. In parallel, we were developing a research collaboration with Carl June and his team at UPenn. The rest is history, and it has been amazing to see the impact on patients.
[What about that initial data made the biggest impression on you?]
Initially we saw patients with literally kilograms of tumor burden. After [CD19 CAR-T] therapy it was melting away! By this time, I'd been at Novartis for about 8 years. I had developed a sense for the speed at which we moved, which until this point was not that fast. To then see the organization so swiftly pivot [to diligence for this cell therapy]—it was incredible. I was at Penn the day that Carl [June] announced the news that Emily Whitehead's cancer was in remission. This was a solidifying moment where I felt like this modality would be bigger than we could have imagined. Again, it was fascinating to see people from all parts of the organization come together. There is no script or playbook for this scenario--but we felt that we were defining a new landscape of medicine. It was an incredible time.
[On the competitive nature of industry]
As soon as other companies started coming on board, there was an internal drive to win the race. There was so much to focus on, but we had some good luck and things fell into place. For example, we were able to [acquire] a Dendreon facility for cell manufacturing. There was a lot of pressure to map out all the logistics, capabilities needed, supply chain, chain of identity, regulatory requirements, clinical plans, etc., to define the path towards registration, but also a lot of excitement for patients. We kept hearing amazing clinical stories that literally brought tears to peoples’ eyes. Penn was reporting 94% CR rates in its pediatric populations, and we were getting over 80 percent responses as well. This was crucial because often smaller academic trials don’t replicate in larger industry-led studies. We went to the ODAC in 2016, and the prep work we did for that was phenomenal. It was very stressful because there wasn’t a playbook, and we were trying to prepare for every question possible. The actual ODAC experience was overwhelming, and the unanimous 10-0 vote spoke volumes about this innovative breakthrough. Tim Cripe, [member of the FDA advisory panel and Chief of Hematology & Oncology at Ohio State], said “This is probably the most exciting thing I have seen in my lifetime”.
[What was it like to be working at Novartis during the approval of Kymriah in 2017?]
It was so exhilarating! The energy level at the company was palpable, even after the ODAC [prior to approval]. When we got the actual approval, it was global news—Forbes, New York Times and every outlet was reporting it. I feel lucky to have gotten that experience and more importantly, to truly be making a difference for patients. As a team, we felt like we could conquer anything as we started changing the practice of medicine. Looking back, it still feels surreal at times. There were definitely several company parties afterwards! Across the different campuses they also had big Kymriah stickers and posters put up everywhere so that everyone felt like they were sharing in the achievement. It was such an inspiring time.
With respect to oncology, where are we now in terms of cell therapy? What were the biggest milestones in the past few years and landmark approvals?
There have been a number of approvals for B cell malignancies with CD19 and BCMA targeted therapies, with six approved products. Because B cells naturally interact with T cells, destroying [B cells] with CARTs can be quite effective. What we also learned from the target profile of CD19 and BCMA, is that B cells are dispensable. You can manage B cell deficiency with intravenous immunoglobulins [IVIG] and other treatments—this has helped pave the way for multiple products across multiple indications and we’re now exploring development in autoimmunity as well.
[What are the different factors you look for in these cell therapies?]
In oncology indications, you need to examine the depth of depletion and the persistence or durability of the CAR-T. Persistence and durability [of the CAR-T] really matter in terms of achieving responses and lasting remissions for patients. There are differences in responses from indication to indication, and how quickly those occur. For example, in the multiple myeloma space, targeting BCMA can lead to responses that evolve over the course of 3 to 9 months. However, with CD19 as a target, deep clinical responses can happen more quickly, within 1 to 3 months.
Considering the target product profile is essential: when you move into the allogeneic space, durability can be affected—the modified T cells don’t persist. The big question in oncology is how we maintain that durability as we create new products? For autoimmune indications, where we want to use CAR-Ts to achieve an “immune reset,” there are even more unanswered questions. What level of durability and B cell depletion is needed? How long do you need to promote B cell aplasia before you get a normal repertoire returning? Will allogeneic or even other approaches like bispecifics [antibodies] be useful? We've learned from oncology, that we do get longer lasting responses with CAR-Ts compared to bispecifics. In autoimmunity there may be additional benefits in not having a persistent CAR-T around [which may favor alternative approaches] though we don’t know all the rules yet in the factors required for transformative benefit.
What are the biggest scientific barriers for cell therapies? What are some broad strategies Novartis is taking to overcome these?
With the first approval of Kymriah, we realized that autologous cell therapy can really have curative potential. To make these treatments available to as many patients as possible, we had to make that process [leukapheresis, engineering, expansion, delivery] more scalable.
One big area of focus for us was to innovate around the cell manufacturing: faster turnaround times while retaining all the best aspects of the T cell biology. This is how we evolved the T-Charge platform: we now have two assets in the clinic using this technology, including the CD19 product YTB323. What we have done [with T-Charge] is to have the cell expansion occur in the patient, as opposed to ex vivo in the lab. We have found that this increases our response rates dramatically and improves response durability.
What we are focused on now is continuing to leverage this [T-Charge] platform as we move to solid tumors, which is another big area of focus for us. We did a partnership with Legend Biotech last year to develop a CAR-T for small cell lung cancer. We are going after DLL-3, which is a clinically validated solid tumor target. Our hope is that combining the T-charge platform with this novel CART will provide more benefit to SCLC patients.
The area of solid tumors is really interesting, because that's where the CAR-T field actually started back in the early 2000s. These initial attempts suffered from a lot of on-target, off-tumor toxicity. But we have now come full circle and are again attempting to tackle these diseases. The field is starting to see signals of activity, though it is still early. It is up to all of us to build on those early signals and tackle different components of what might be limiting as we strive to make more impact on the lives of patients battling these terrible diseases.
In 25 years, what will the field of cell and gene therapy look like?
Cell and gene is a fast-changing field with new developments in synthetic biology, delivery systems, and gene editing. A key challenge is how to make safe and effective therapies that are easy to deliver to patients, even in the community setting. I hope that in 25 years, personalized medicine helps us match patients with the right therapies, and the therapies are available when needed, either through radically simplified ex vivo delivery or new in vivo methods. I'm also optimistic about the prospects for patients who have no other options, and hope we can overcome the historical obstacles of solid tumors and extend to non-oncology areas where curative potential is possible.
What are some broad areas of science outside of your work at Novartis in C> that you are excited about?
Definitely neuroscience and neuroinflammation. We continue to uncover unique ways in which the immune system impacts disease and the complex relationship between the brain, inflammation and various neurological disorders is truly fascinating. As the field continues to evolve with better tools, deeper mechanistic insights and potential therapeutic strategies, I’m excited to see where these might lead to transformative benefit for patients.
Any pieces of advice for a trainee in science and medicine looking to make an impact in industry?
Think about what you love, what brings you joy. Then reflect on your natural talents—what you’re really good at and what energizes you. Use these strengths to guide you in a direction that inspires you every day. Notice what sparks your interest and use this to find your path and your North Star. It may be a winding path with challenges and setbacks. But if you follow your passion, you stay true to yourself and will overcome the obstacles.